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The objective of this study was to evaluate the prognostic value of ARID1A, p53, p21, p16 and ß-Catenin in endometrioid and clear cell ovarian and endometrial carcinomas. 97 tumors were available for analysis of ARID1A, p53, p21, p16 and ß-Catenin with the techniques of tissue microarray and immunohistochemistry. 32 were ovarian carcinomas and 65 were endometrial carcinomas. Endometrioid ovarian carcinomas showed negative staining for ARID1A (a) and p21 (b), aberrant expression of p53 (c) and p16 (d) and ß-Catenin positive nuclear expression (e) respectively in 19% (a), 100% (b), 28.6% (c), 52.4% (d) and 4.8% (e) of all cases. In the group of clear cell ovarian carcinomas it was 63.6% (a), 100% (b), 81.8% (c), 54.5% (d) and 0% (e). For endometrioid uterine carcinomas it was 75.7% (a), 94.9% (b), 30.5% (c), 52.1% (d) and 6.8% (e) and for clear cell uterine carcinomas it was 8.6% (a), 100% (b), 50% (c), 100% (d) and 0% (e). Survival analysis showed that negative expression of ARID1A, p53 aberrant expression and ß-Catenin nuclear positive staining are independent negative prognosticators in both, clear cell and endometrioid carcinoma, regardless of ovarian or uterine origin. Cox-Regression analysis showed them again as negative prognostic factors. Furthermore, we found a significant correlation between ARID1A and ß-Catenin expression in endometrioid uterine tumors. The analyzed gynaecological carcinoma showed a distinct expression scheme of proteins that are associated with tumor suppression. We may conclude that ARID1A, p53 and ß-Catenin are the strongest prognostic factors by analyzing a subgroup of tumor suppressor genes in clear cell and endometrioid subtypes of ovarian and endometrial cancer and may be used along with traditional morphological and clinical characteristics for prognosis.

In recurrent epithelial ovarian cancer (EOC) most patients develop platinum-resistance. On molecular level the NRF2 pathway, a cellular defense mechanism against reactive oxygen species, is induced. In this study, we investigate AKR1C1/2, target of NRF2, in a well-established EOC collective by immunohistochemistry and in a panel of ovarian cancer cell lines including platinum-resistant clones. The therapeutic effect of carboplatin and MPA as monotherapy or in combination was assessed by functional assays, using OV90 and OV90cp cells. Molecular mechanisms of action of MPA were investigated by NRF2 silencing and AKR activity measurements. Immunohistochemical analysis revealed that AKR1C1/2 is a key player in the development of chemoresistance and an independent indicator for short PFS (23.5 vs. 49.6 months, p = 0.013). Inhibition of AKR1C1/2 by MPA led to a concentration- and time-dependent decline of OV90 viability and to an increased response to CP in vitro. By NRF2 silencing, however, the effects of MPA treatment were reduced. Concludingly, our data suggest that a combination therapy of carboplatin and MPA might be a promising therapeutic approach to increase response rates of EOC patients, which should be explored in clinical context.

The vitamin D receptor (VDR), primarily known as a crucial mediator of calcium homeostasis and metabolism, has been shown to play a significant role in various cancer entities. Previous studies have focused on vitamin D and its receptor in gynecological cancers, noting that the receptor is upregulated in epithelial ovarian cancer (EOC). The aim of this study is to analyze the prognostic impact of VDR and its functional significance in ovarian cancer. Through immunohistochemistry, VDR staining was examined in 156 ovarian cancer samples. Evaluation of VDR staining was conducted in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score, and the scores were classified into high- and low-level expressions. Expression levels were correlated with clinical and pathological parameters as well as with overall survival to assess for prognostic impact. Differences in cytoplasmic VDR expression were identified between the histological subtypes (p = 0.001). Serous, clear cell, and endometrioid subtypes showed the highest staining, while the mucinous subtype showed the lowest. Cytoplasmic VDR correlated with higher FIGO stage (p = 0.013; Cc = 0.203), positive lymph node status (p = 0.023; Cc = 0.236), high-grade serous histology (p = 0.000; Cc = 0.298) and grading from the distinct histological subtypes (p = 0.006; Cc = − 0.225). Nuclear VDR did not correlate with clinicopathological data. High cytoplasmic expression of VDR was associated with impaired overall survival (HR 2.218, 32.5 months vs. median not reached; p < 0.001) and was confirmed as a statistically independent prognostic factor in the Cox regression multivariate analysis. Additional knowledge of VDR as a biomarker and its interactions within the mitogen-activated protein kinase (MAPK) signaling pathway could potentially improve the prognosis of therapeutic approaches for specific subgroups in EOC.

PurposeBreast cancer is the leading cause of cancer death in females. Histone modifications have been shown to have an influence on the gene expression. This study focusses on the histone modifications H3K9ac and H3K4me3 in breast cancer and their impact on survivalMethodsH3K4me3 and H3K9ac expression was immunohistochemically examined in 235 tissue samples.ResultsPositive estrogen receptor status was correlated with a higher IRS of the nuclear (p = 0.033), and of the cytoplasmic H3K4me3 staining (p = 0.009). H3K9ac intensity was associated to the Her2 status (p = 0.045) and to poor prognosis in cells with positive Ki67 status (p = 0.013). A high intensity of nuclear H3K4me3 staining was found to be correlated with a lower 10-year-survival (p = 0.026) and with lower breast cancer-specific survival (p = 0.004). High percentage score (> 190) of H3K9ac expression was correlated to worse breast cancer-specific survival (p = 0.005). Shorter progression-free survival was found in patients with nuclear (p = 0.013) and cytoplasmic H3K4me3expression (p = 0.024) and H3K9ac expression (p = 0.023).ConclusionThis analysis provides new evidence of histone modifications in breast cancer. High H3K4me3 and H3K9ac expression was correlated with survival rates. Further investigation of histone modifications in breast cancer could lead to a more profound understanding of the molecular mechanisms of cancer development and could result in new therapeutic strategies.

Background Regulatory T cells (Treg) suppress cytotoxic T cell anti-tumoral immune responses and thereby promote tumor progression. Prevention of intratumoral Treg accumulation by inhibition of their migration to the tumor microenvironment is a promising therapeutic strategy. The aim of this study was to identify the role of the two major Treg-attracting chemokines CCL1 and CCL22 in human breast cancer. Methods One hundred ninety-nine tissue samples of patients with invasive breast cancer were stained for CCL1 and CCL22 by immunohistochemistry. Chemokine expression and tumor infiltration by regulatory T cells, determined by expression of the transcription factor FoxP3, were quantified and their correlation to clinical features was statistically analyzed. Results Both CCL1 and CCL22 were expressed in most breast cancer tissues. CCL1 was significantly over-expressed in invasive breast cancer as compared to normal breast tissue. CCL1, but surprisingly not CCL22, showed a significant correlation with the number of tumor-infiltrating FoxP3+ Treg ( p < 0.001). High numbers of intratumoral CCL1 expressing cells were related to high grade tumors (G4) and a positive estrogen receptor (ER) status whereas high CCL22 expression was generally seen in lower grade tumors. The median survival of 88 patients with high intratumoral CCL1 expression was 37 months compared to 50 months for the 87 patients with low CCL1 levels, this trend was however not statistically significant. Conclusions We found a high expression of CCL1 in human breast cancer. CCL1 significantly correlated with the infiltration of immunosuppressive FoxP3+ Treg, that are known to negatively affect survival. Thus, CCL1 may serve as prognostic marker and novel therapeutic target in breast cancer.

Targeting the tumor-associated carbonic anhydrase XII (CA XII) is considered a promising strategy to improve cancer treatment. As such progress is highly demanded for ovarian carcinomas, the present study aimed to provide deeper information about their CA XII expression profile. A large collection of tissue specimens was stained immunohistochemically with a specific anti-CA XII antibody to evaluate the expression in neoplastic and non-neoplastic epithelial ovarian cells. In addition, flow cytometry was used to measure CA XII expression on tumor cells from malignant ascites fluid. Binding of the antibody revealed a significant CA XII expression in most ovarian carcinoma tissue samples and ascites-derived ovarian carcinoma cells. Moreover, CA XII was expressed at higher levels in ovarian carcinomas as compared to borderline ovarian tumors and non-neoplastic ovarian epithelia. Within the carcinoma tissues, high expression of CA XII was associated with higher tumor grading and a trend towards shorter overall survival. Our results indicate that CA XII plays a crucial role for the malignancy of ovarian carcinoma cells and emphasize the potential of CA XII as a diagnostic marker and therapeutic target in the management of ovarian carcinomas.

Purpose Thyroid hormone receptors (THR) have manifold functions and are involved in the carcinogenesis of several tumor types. Within this study, we aimed to investigate the expression pattern (nuclear versus cytoplasmic) of the THR alpha and its impact on patients survival in ovarian cancer (OvCa).MethodsThe presence of the thyroid hormone receptors THRα, THRα1 and − 2 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated with clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS).ResultsAmong all subtypes of OvCa, clear cell carcinomas showed the highest THRα expression. Furthermore, nuclear THRα was associated with a reduced survival in this subtype. However, nuclear expressed THRα1 turned out to be a positive prognosticator for all subtypes of OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. In contrast, cytoplasmic expression THRα2 was associated with a reduced OS in all subtypes of OvCa patients; while, cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates with gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin.ConclusionDepending on nuclear or cytoplasmic expression, our study shows that THRα and its isoforms 1 and 2 provide different prognostic information for ovarian cancer patients. Further investigations should analyze if THRs may represent new endocrine targets for the treatment of ovarian cancer.

Prostaglandin induced signalling is involved in different cancers. As previously described, the EP3 receptor expression decreases with increasing stage of cervical intraepithelial lesions (CIN). In addition, in cervical cancer EP3 is an independent prognosticator for overall survival and correlates with FIGO stages. Currently the role of Prostaglandin 2 receptor 2 (EP2) in CIN is unknown. The aim of this study was to analyse the expression of EP2 for potential prognostic value for patients with cervical dysplasia. EP2 expression was analysed by immunohistochemistry in 33 patient samples (CIN1–3) using the immune-reactivity scoring system (IRS). Expression levels were correlated with clinical outcome to analyse prognostic relevance in patients with CIN2. Data analysis was performed using non parametric Kruskal–Wallis and Spearman rank sum test. Cytoplasmic expression levels of EP2 correlated significantly (p < 0.001) with different grades of cervical dysplasia. Median EP2-IRS in CIN1 was 2 (n = 8), 3 in CIN2 (n = 9) and 6 in CIN3 (n = 16). Comparing regressive (n = 3, median IRS = 2) to progressive (n = 6, median IRS = 4) CIN2 cases the median IRS differed significantly (p = 0.017). Staining intensity (p = 0.009) and IRS (p = 0.005) of EP2 and EP3 correlate inversely. EP2 expression level significantly increases with higher grade of CIN and could qualify as a potential prognostic marker for the regressive or progressive course in CIN2 lesions. These findings emphasize the significant role of PGE2 signalling in CIN and could help to identify targets for future therapies.

The evaluation of new prognostic factors that can be targeted in ovarian cancer diagnosis and therapy is of the utmost importance. Galectins are a family of carbohydrate binding proteins with various implications in cancer biology. In this study, the presence of galectin (Gal)-8 and -9 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC). Staining was evaluated using semi-quantitative immunoreactivity (IR) scores and correlated to clinical and pathological data. Different types of galectin expression were compared with respect to disease-free survival (DFS) and overall survival (OS). Gal-8 served as a new positive prognostic factor for the OS and DFS of ovarian cancer patients. Gal-9 expression determined the DFS and OS of ovarian cancer patients in two opposing ways—moderate Gal-9 expression was correlated with a reduced outcome as compared to Gal-9 negative cases, while patients with high Gal-9 expression showed the best outcome.

AimProgrammed death-ligand 1 (PD-L1) has become a widely used predictive biomarker for therapy with checkpoint inhibitors in a variety of cancers. Here, we studied the expression of PD-L1 in squamous cell carcinomas of the vulva (SCCV) with regard to HPV status via its surrogate marker p16. Additionally, the status of PD-L1 and p16 were analyzed for prognostic information and potential correlation to tumor-infiltrating lymphocytes (TILs).MethodsPD-L1 was analyzed in 128 cases of SCCV using the tumor proportion score (TPS), the immune cell score (ICS) and the combined positive score (CPS). Cases were immunostained for p16 and analyzed for stromal TILs. PD-L1, p16, and TILs were compared to clinico-pathological parameters and patient’s survival.ResultsTPS ≥ 50% and CPS ≥ 50 were correlated to a worse grading (p = 0.028 and p = 0.031), but not to FIGO-stage. CPS ≥ 50 was associated to a worse prognosis with overall survival (p = 0.021) but was not correlated to the progression-free survival. P16-positivity was correlated to a longer progression-free survival (p = 0.006) and overall survival (p = 0.023). PD-L1 expression was independent from p16 status. TILs ≥ 50% were present in 24% of the cases and were strongly correlated to PD-L1 (TPS p = 0.02, ICS p < 0.001, CPS p = 0.001).ConclusionOur data demonstrate that PD-L1 expression is frequent in SCCV and independent from p16 status. High PD-L1 expression was associated with an unfavorable outcome whereas p16-positivity turned out to be an independent positive prognostic factor.